Early detection of cancer and precancerous conditions improves patient survival. This study will identify a set of peptides and proteins (P/P) in serum associated with hepatocellular carcinoma (HCC). To achieve this goal, we developed enrichment of the low molecular weight (LMW) serum fraction for matrix assisted laser desorption ionization-time of flight (MALD1-TOF/TOF) mass spectrometric (MS) identification of biomarkers. This method allows high-throughput screening of a population as well as identification of the peptides of interest by TOF/TOF sequencing. We tested the biomarker discovery method on a pilot set of HCC cases and matched controls from our unique study of HCC in Egypt, a country with an epidemic of hepatitis C viral infection. The pilot-study identified a set of six peptides that predict HCC with 96% prediction accuracy. In this study, we propose to expand the project and focus on identification of peptides associated with malignant conversion of liver cirrhosis. Our goal is to identify biomarkers that would improve early detection of HCC in this high-risk group and track the natural progression of chronic viral hepatitis to cancer. We will cross validate our ongoing study in Egypt with a study of HCC in the US population;verify peptide- identification by MALDI-TOF/TOF sequencing, complementary liquid chromatography/mass spectrometry, synthesis of peptides standards, and immunodepletion;develop improved methods for quantification of the peptides;and test performance of the biomarker-candidates. Defining clinically applicable biomarkers of early-stage cancer has potentially far-reaching consequences for disease management and patient health. The biomarkers could be used to screen high risk populations for early signs of disease;to design and test new chemoprevention strategies;and to follow disease progression after treatment. Identification of the P/P is expected to generate new hypotheses for targeted disease management.